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  1. Article ; Online: The RNA cap methyltransferases RNMT and CMTR1 co-ordinate gene expression during neural differentiation.

    Liang, Shang / Almohammed, Rajaei / Cowling, Victoria H

    Biochemical Society transactions

    2023  Volume 51, Issue 3, Page(s) 1131–1141

    Abstract: Regulation of RNA cap formation has potent impacts on gene regulation, controlling which transcripts are expressed, processed and translated into protein. Recently, the RNA cap methyltransferases RNA guanine-7 methyltransferase (RNMT) and cap-specific ... ...

    Abstract Regulation of RNA cap formation has potent impacts on gene regulation, controlling which transcripts are expressed, processed and translated into protein. Recently, the RNA cap methyltransferases RNA guanine-7 methyltransferase (RNMT) and cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 1 (CMTR1) have been found to be independently regulated during embryonic stem (ES) cell differentiation controlling the expression of overlapping and distinct protein families. During neural differentiation, RNMT is repressed and CMTR1 is up-regulated. RNMT promotes expression of the pluripotency-associated gene products; repression of the RNMT complex (RNMT-RAM) is required for repression of these RNAs and proteins during differentiation. The predominant RNA targets of CMTR1 encode the histones and ribosomal proteins (RPs). CMTR1 up-regulation is required to maintain the expression of histones and RPs during differentiation and to maintain DNA replication, RNA translation and cell proliferation. Thus the co-ordinate regulation of RNMT and CMTR1 is required for different aspects of ES cell differentiation. In this review, we discuss the mechanisms by which RNMT and CMTR1 are independently regulated during ES cell differentiation and explore how this influences the co-ordinated gene regulation required of emerging cell lineages.
    MeSH term(s) Cell Differentiation ; Histones/metabolism ; Methyltransferases/genetics ; Methyltransferases/metabolism ; RNA Caps/genetics ; RNA Caps/metabolism ; Transcription, Genetic ; Humans ; Animals
    Chemical Substances Histones ; Methyltransferases (EC 2.1.1.-) ; RNA Caps
    Language English
    Publishing date 2023-05-05
    Publishing country England
    Document type Review ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 184237-7
    ISSN 1470-8752 ; 0300-5127
    ISSN (online) 1470-8752
    ISSN 0300-5127
    DOI 10.1042/BST20221154
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 944: Show issues Location:
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  2. Article ; Online: CMTR1 is recruited to transcription start sites and promotes ribosomal protein and histone gene expression in embryonic stem cells.

    Liang, Shang / Silva, Joana C / Suska, Olga / Lukoszek, Radoslaw / Almohammed, Rajaei / Cowling, Victoria H

    Nucleic acids research

    2022  Volume 50, Issue 5, Page(s) 2905–2922

    Abstract: CMTR1 (cap methyltransferase 1) catalyses methylation of the first transcribed nucleotide of RNAPII transcripts (N1 2'-O-Me), creating part of the mammalian RNA cap structure. In addition to marking RNA as self, N1 2'-O-Me has ill-defined roles in RNA ... ...

    Abstract CMTR1 (cap methyltransferase 1) catalyses methylation of the first transcribed nucleotide of RNAPII transcripts (N1 2'-O-Me), creating part of the mammalian RNA cap structure. In addition to marking RNA as self, N1 2'-O-Me has ill-defined roles in RNA expression and translation. Here, we investigated the gene specificity of CMTR1 and its impact on RNA expression in embryonic stem cells. Using chromatin immunoprecipitation, CMTR1 was found to bind to transcription start sites (TSS) correlating with RNAPII levels, predominantly binding at histone genes and ribosomal protein (RP) genes. Repression of CMTR1 expression resulted in repression of RNAPII binding at the TSS and repression of RNA expression, particularly of histone and RP genes. In correlation with regulation of histones and RP genes, CMTR1 repression resulted in repression of translation and induction of DNA replication stress and damage. Indicating a direct role for CMTR1 in transcription, addition of recombinant CMTR1 to purified nuclei increased transcription of the histone and RP genes. CMTR1 was found to be upregulated during neural differentiation and there was an enhanced requirement for CMTR1 for gene expression and proliferation during this process. We highlight the distinct roles of the cap methyltransferases RNMT and CMTR1 in target gene expression and differentiation.
    MeSH term(s) Animals ; Embryonic Stem Cells/metabolism ; Gene Expression ; Histones/genetics ; Histones/metabolism ; Mammals/genetics ; Methyltransferases ; RNA Caps/genetics ; RNA Polymerase II/metabolism ; Ribosomal Proteins/genetics ; Ribosomal Proteins/metabolism ; Transcription Initiation Site ; Transcription, Genetic
    Chemical Substances Histones ; RNA Caps ; Ribosomal Proteins ; Methyltransferases (EC 2.1.1.-) ; RNA Polymerase II (EC 2.7.7.-)
    Language English
    Publishing date 2022-02-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkac122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1067: Show issues Location:
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  3. Article ; Online: A novel RNA pol II CTD interaction site on the mRNA capping enzyme is essential for its allosteric activation.

    Bage, Marcus G / Almohammed, Rajaei / Cowling, Victoria H / Pisliakov, Andrei V

    Nucleic acids research

    2020  Volume 49, Issue 6, Page(s) 3109–3126

    Abstract: Recruitment of the mRNA capping enzyme (CE/RNGTT) to the site of transcription is essential for the formation of the 5' mRNA cap, which in turn ensures efficient transcription, splicing, polyadenylation, nuclear export and translation of mRNA in ... ...

    Abstract Recruitment of the mRNA capping enzyme (CE/RNGTT) to the site of transcription is essential for the formation of the 5' mRNA cap, which in turn ensures efficient transcription, splicing, polyadenylation, nuclear export and translation of mRNA in eukaryotic cells. The CE GTase is recruited and activated by the Serine-5 phosphorylated carboxyl-terminal domain (CTD) of RNA polymerase II. Through the use of molecular dynamics simulations and enhanced sampling techniques, we provide a systematic and detailed characterization of the human CE-CTD interface, describing the effect of the CTD phosphorylation state, length and orientation on this interaction. Our computational analyses identify novel CTD interaction sites on the human CE GTase surface and quantify their relative contributions to CTD binding. We also identify, for the first time, allosteric connections between the CE GTase active site and the CTD binding sites, allowing us to propose a mechanism for allosteric activation. Through binding and activity assays we validate the novel CTD binding sites and show that the CDS2 site is essential for CE GTase activity stimulation. Comparison of the novel sites with cocrystal structures of the CE-CTD complex in different eukaryotic taxa reveals that this interface is considerably more conserved than previous structures have indicated.
    MeSH term(s) Allosteric Regulation ; Animals ; Binding Sites ; Catalytic Domain ; Enzyme Activation ; Humans ; Mice ; Molecular Dynamics Simulation ; Nucleotidyltransferases/chemistry ; Nucleotidyltransferases/metabolism ; Phosphorylation ; Phosphoserine/chemistry ; Phosphoserine/metabolism ; Phycodnaviridae/enzymology ; Protein Binding ; Protein Conformation ; Protein Domains ; RNA Polymerase II/chemistry ; RNA Polymerase II/metabolism
    Chemical Substances Phosphoserine (17885-08-4) ; Nucleotidyltransferases (EC 2.7.7.-) ; RNA Polymerase II (EC 2.7.7.-) ; mRNA guanylyltransferase (EC 2.7.7.50)
    Language English
    Publishing date 2020-08-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkab130
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1067: Show issues Location:
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  4. Article ; Online: Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta.

    Almohammed, Rajaei / Osborn, Kay / Ramasubramanyan, Sharada / Perez-Fernandez, Ijiel Barak Naranjo / Godfrey, Anja / Mancini, Erika J / Sinclair, Alison J

    The Journal of general virology

    2018  Volume 99, Issue 6, Page(s) 805–817

    Abstract: The human gamma herpes virus Epstein-Barr virus (EBV) exploits multiple routes to evade the cellular immune response. During the EBV lytic replication cycle, viral proteins are expressed that provide excellent targets for recognition by cytotoxic T cells. ...

    Abstract The human gamma herpes virus Epstein-Barr virus (EBV) exploits multiple routes to evade the cellular immune response. During the EBV lytic replication cycle, viral proteins are expressed that provide excellent targets for recognition by cytotoxic T cells. This is countered by the viral BNLF2a gene. In B cells during latency, where BNLF2a is not expressed, we show that its regulatory region is embedded in repressive chromatin. The expression of BNLF2a mirrors the expression of a viral lytic cycle transcriptional regulator, Zta (BZLF1, EB1, ZEBRA), in B cells and we propose that Zta plays a role in up-regulating BNLF2a. In cells undergoing EBV lytic replication, we identified two distinct regions of interaction of Zta with the chromatin-associated BNLF2a promoter. We identify five potential Zta-response elements (ZREs) in the promoter that are highly conserved between virus isolates. Zta binds to these elements in vitro and activates the expression of the BNLF2a promoter in both epithelial and B cells. We also found redundancy amongst the ZREs. The EBV genome undergoes a biphasic DNA methylation cycle during its infection cycle. One of the ZREs contains an integral CpG motif. We show that this can be DNA methylated during EBV latency and that both Zta binding and promoter activation are enhanced by its methylation. In summary, we find that the BNLF2a promoter is directly targeted by Zta and that DNA methylation within the proximal ZRE aids activation. The implications for regulation of this key viral gene during the reactivation of EBV from latency are discussed.
    MeSH term(s) B-Lymphocytes/virology ; DNA Methylation ; Epigenesis, Genetic ; Gene Expression Regulation, Viral ; Genome, Viral ; HEK293 Cells ; HeLa Cells ; Herpesvirus 4, Human/genetics ; Herpesvirus 4, Human/immunology ; Herpesvirus 4, Human/physiology ; Humans ; Immune Evasion ; Promoter Regions, Genetic ; Trans-Activators/genetics ; Trans-Activators/physiology ; Transcriptional Activation ; Viral Matrix Proteins/genetics ; Viral Matrix Proteins/physiology ; Virus Latency/genetics ; Virus Replication/genetics
    Chemical Substances BNLF21 protein, human herpesvirus 4 ; BZLF1 protein, Herpesvirus 4, Human ; Trans-Activators ; Viral Matrix Proteins
    Language English
    Publishing date 2018-03-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001056
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 610: Show issues Location:
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